Outlook for New CAR-Based Therapies with a Focus on CAR NK Cells: What Lies Beyond CAR-Engineered T Cells in the Race against Cancer

Abstract

Chimeric antigen receptor (CAR) engineering of T cells has revolutionized the field of cellular therapy for the treatment of cancer. Despite this success, autologous CAR-T cells have recognized limitations that have led to the investigation of other immune effector cells as candidates for CAR modification. Recently, natural killer (NK) cells have emerged as safe and effective platforms for CAR engineering. In this article, we review the advantages, challenges, and preclinical and clinical research advances in CAR NK cell engineering for cancer immunotherapy. We also briefly consider the feasibility and potential benefits of applying other immune effector cells as vehicles for CAR expression. SIGNIFICANCE: CAR engineering can redirect the specificity of immune effector cells, converting them to a much more potent weapon to combat cancer cells. Expanding this strategy to immune effectors beyond conventional T lymphocytes could overcome some of the limitations of CAR T cells, paving the way for safer and more effective off-the-shelf cellular therapy products.

Figure 1.

NK cell specific signaling domains incorporated within CAR intracellular domains Image created in BioRender.com Abbreviations: DAP12, DNAX Activating Protein of 12KDa; DAP10, DNAX Activating Protein of 12KDa; ITAM, immunoreceptor tyrosine-based activation motif; ITSM, immunoreceptor tyrosine-based switch motif; YXXM, Y stands for tyrosine, X for any amino acid residue, and M for methionine; TRAF1–3, tumor necrosis factor receptor-associated factors 1, 2 and 3.

Figure 2.

Track record of alternative CAR based therapies Image created in BioRender.com